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1 684 ORIGINAL CONTRIBUTIONS nature publishing group see related editorial on page x Peptic Ulcer Bleeding Risk. The Role of Helicobacter Pylori Infection in NSAID/Low-Dose Aspirin Users C. Sostres, MD 1, P. Carrera-Lasfuentes, PhD 2, R. Benito, MD 3, P. Roncales 4, M. Arruebo, MD 4, M.T. Arroyo, MD 1, L. Bujanda, MD 5, L.A. García-Rodríguez, MD 6 and A. Lanas, MD 1, 2, 4 OBJECTIVES: METHODS: RESULTS: Helicobacter pylori ( H. pylori) infection and NSAID/low-dose aspirin (ASA) use are associated with peptic ulcer disease. The risk of peptic ulcer bleeding (PUB) associated with the interaction of these factors remains unclear. The objective of this study was to determine the risk of PUB associated with the interaction between H. pylori infection and current nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose ASA use. This was a case-control study of consecutive patients hospitalized because of PUB. Controls were matched by age, sex, and month of admission. H. pylori infection status was determined in all cases and controls by serology. Drug use was determined by structured questionnaire. Adjusted relative risk (RR) associated with different factors, and the interaction between NSAID/ASA and H. pylori infection was estimated by logistic regression analysis. The study included 666 cases of PUB and 666 controls; 74.3% cases and 54.8% controls (RR: 2.6; 95% confidence interval (CI): ) tested positive for H. pylori infection; 34.5% of cases had current NSAID use compared with 13.4% of controls (RR: 4.0; 95% CI: ). Respective proportions for low-dose ASA use were 15.8 and 12%, respectively (RR: 1.9; 95% CI: ). The RR of PUB for concomitant NSAID use and H. pylori infection suggested an additive effect (RR: 8.0; 95% CI: ), whereas no interaction was observed with ASA use (RR: 3.5; 95% CI: ). CONCLUSIONS: NSAID, low-dose ASA use, and H. pylori infection are three independent risk factors for the development of PUB, but there were differences in the interaction effect between low-dose ASA (no interaction) or NSAID (addition) use and H. pylori infection, which may have implications for clinical practice in prevention strategies. Am J Gastroenterol 2015; 110: ; doi: /ajg ; published online 21 April 2015 INTRODUCTION Helicobacter pylori (H. pylori ) infection, nonsteroidal antiinflammatory drugs (NSAIDs), and low-dose aspirin (ASA) use are three independent and the most important modifiable risk factors in the pathogenesis of gastroduodenal peptic ulcers ( 1 ). In clinical practice, the coincidence of H. pylori infection with the intake of one of those drugs in the same patient is frequent and may have important clinical consequences. In this way, whether NSAID intake in the presence of H. pylori infection may further increase the risk of peptic ulcer is still under intense debate. Clinicians might expect at least an additive if not a synergistic effect on the risk of peptic ulcer. However, despite H. pylori and NSAID sharing a number of pathogenic mechanisms, studies on the interaction between these two risk factors has yielded conflicting data leaving this relationship uncertain ( 2 ). In addition, in the last years, the use of low-dose ASA has increased as a result of accumulating evidence for its benefits in primary and secondary prevention of cardiovascular and cerebrovascular events ( 3 5 ). Low-dose ASA damages the upper gastrointestinal (GI) tract through both local and systemic effects ( 4,5 ). Although it is commonly asserted that H. pylori infection will increase the risk of ASA-associated GI side effects, the impact and influence of H. pylori infection on the incidence of upper GI bleeding (UGIB) in patients taking ASA is also still unclear ( 6 ). These conflicting 1 Universitary Hospital Lozano Blesa, Gastroenterology Unit, Zaragoza, Spain ; 2 CIBERehd, Madrid, Spain ; 3 Universitary Hospital Lozano Blesa, Microbiology Unit, Zaragoza, Spain ; 4 Health Science Institute of Aragon, Zaragoza, Spain ; 5 Universitary Hospital of Donostia, San Sebastian, Spain ; 6 CEIFE, Madrid, Spain. Correspondence: C. Sostres, MD, Universitary Hospital Lozano Blesa, Gastroenterology Unit, Calle San Juan Bosco 15, Zaragoza 50009, Spain. Received 13 October 2014 ; accepted 14 February 2015 The American Journal of GASTROENTEROLOGY VOLUME 110 MAY

2 Peptic Ulcer Bleeding in Low-Dose Aspirin/NSAID Users 685 data are the result of variability in methods, selection biases, and outcome definition. Furthermore, most studies involve a limited number of patients. A highly quoted meta-analysis ( 7 ) analyzed all available endoscopic studies at that time but included only a limited number of studies with serious outcomes such as UGIB. Therefore, we aimed at evaluating the risk of peptic ulcer bleeding (PUB) associated with the interaction between H. pylori infection and current use of NSAIDs or low-dose ASA in a large group of patients presenting with PUB requiring hospitalization. METHODS Study design and population Hospital-based, case control study with prospective case ascertainment and data collection carried out between 2006 and Cases and controls were collected in three general hospitals of the Spanish National Health System. Eligible participants were year old and free of liver disease, coagulation disorders, or malignancies in the previous 5 years. Definitions Case. Patient hospitalized because of major UGIB (hematemesis or melena), which was confirmed by hospital personnel and caused by a peptic ulcer lesion as determined in an endoscopic procedure. Cases with the following conditions were excluded: (a) any other cause of bleeding (gastro-esophageal varices, vascular lesions, tumors, Mallory Weiss, associated coagulopathy, and esophagitis); (b) patients with unreliable sources of information; (c) patients refusing to participate; and (d) in-hospital bleeding patients. The index date was the first day when the GI bleeding episode was objectively noticed. Control. Controls matched by age (±5 years), gender, hospital, and month of admission were selected. Controls were obtained either from people accompanying hospitalized patients or from unselected people referred to the hospital outpatient s office for blood extraction as part of general analysis. The index date for controls was the day of the interview. Exposure. Drug use was considered to be current when the drug was taken up to 7 days before the index date. It was considered to be past when the use ended earlier than 1 week before the index date. Non-use was individual referring no mention of drug use. Cardioprotective ASA (low dose) was defined as any dose no greater than 300 mg/day. hospital reports that confirmed the diagnosis. All of these groups were mutually exclusive. Data collection Cases and controls were interviewed by the same persons (a gastroenterologist or a gastroenterology trainee) in each participating center, in general, within 48 h of admission. To ensure reliable data collection, cases and controls were accompanied during the interview by a relative or someone who lived with them. A structured questionnaire of marketed drugs and a careful review of prescriptions were used. Interview data were completed with the patient s family and hospital clinical records concerning endoscopy data. To avoid bias, interviewers were not involved in the design, were not the investigators at each center of the study, and were unaware of the actual objectives of the study. H. pylori status infection (positive or negative) was determined in all cases and controls by serology ( H. pylori enzyme-linked immunosorbent assay immunoglobulin G, Vircell, Santa Fé, Granada, Spain). In a subset of patients, this test showed a good agreement (kappa coefficient =0.608 with previously validated western blot test (Bioblot Helicobacter Biokit SA, Barcelona, Spain)) in other studies conducted by our group ( 8,9 ). According to the manufacturer information, the test used in this study has 97% sensitivity and 100% specificity. These figures were obtained by comparing our test in local Spanish patients with other enzyme-linked immunosorbent assay test previously validated in the literature ( 10,11 ). Blood samples were obtained at the time of interview. A committee was designated to respond to any questions or doubts arising during the study, and all data were introduced into a single database. Statistical analysis Results of continuous variables are expressed as mean with standard deviation (s.d.), whereas qualitative variables are expressed as frequencies and percentages. Bivariate analysis of all clinical variables and drug use was performed by the chi-square test and Student s t -test. Conditional logistic-adjusted regression analyses were carried out to compute relative risks (RR) of PUB and their 95% confidence intervals (95% CI). The final multivariate model included age, sex, ulcer history, smoking status, proton pump inhibitor use, anticoagulant use, NSAID, and ASA. We assessed interactions between NSAID or low-dose ASA and H. pylori, using one simple term in the model for the join effect. For all tests, a two-sided P -value <0.05 was considered statistically significant. The statistical analyses were performed using the SPSS software v for Windows (SPSS Ibérica, Madrid, Spain). GI disorder history. We cl a ss i fi ed cases and controls as having a history of ulcer, dyspepsia, or neither condition. A person was defined as having no history of GI disorder if he or she reported no history of dyspepsia or ulcer (uncomplicated or complicated) before the index date. A person was defined as having a history of dyspepsia only if he or she did not report also a history of peptic ulcer. Finally, a person was defined as having a history of peptic ulcer with or without complications (bleeding or perforation) when he or she reported so and found or provided previous RESULTS Clinical variables, drug use, and H. pylori infection Overall, 666 cases and 666 controls meeting all eligibility criteria were included in the analysis. Mean Hb level was 9.1±2.4 g/dl, and the mean of transfused blood units was 1.6±2.1 in cases. Table 1 presents frequency distribution and crude and adjusted RRs for age, gender, smoking, complicated or uncomplicated ulcer history, dyspepsia, current drug use, and H. pylori infection status by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

4 Peptic Ulcer Bleeding in Low-Dose Aspirin/NSAID Users 687 Table 3. RRs for the development of either upper gastric or duodenal ulcer bleeding associated with NSAID or ASA use and Helicobacter pylori ( Hp ) infection Factor Gastric ulcer Duodenal ulcer RR a (95% CI) RR a (95% CI) No NSAID No Hp 1 1 NSAID No Hp 6.2 ( ) 2.2 ( ) No NSAID Hp 2.1 ( ) 3.3 ( ) NSAID Hp 8.6 ( ) 7.8 ( ) No ASA No Hp 1 1 ASA No Hp 2.2 ( ) 2.3 ( ) No ASA Hp 2.1 ( ) 3.5 ( ) ASA Hp 2.4 ( ) 6.3 ( ) ASA, aspirin; CI, confi dence interval; NSAID, nonsteroidal anti-infl ammatory drug; RR, relative risk. a Adjusted for age, gender, ulcer history, smoking status, proton pump inhibitors, anticoagulant, NSAIDs, and aspirin use. individual factors alone. Sub-analysis performed with high-dose ASA ( > 500 mg/day) showed similar interaction pattern to that seen with NSAIDs (data not shown). Table 3 shows the adjusted RRs of PUB for the interaction between NSAID or low-dose ASA current use and H. pylori infection, separately for gastric and duodenal ulcer. A synergistic interaction was present between NSAID use and H. pylori infection for the risk of duodenal ulcer bleeding, whereas the effect of these two risk factors was additive for gastric ulcer bleeding. No interaction was observed among ASA users with H. pylori infection for gastric ulcer bleeding, whereas there was an additive effect for duodenal ulcer bleeding. DISCUSSION This large case control study has confirmed that H. pylori infection and NSAID or low-dose ASA current use are independent risk factors for the development of PUB ( 1 ). In our study, lowdose ASA increased the risk of PUB twofold, H. pylori infection threefold, and NSAIDs fourfold. However, the combination between these factors shows that the joint effect between H. pylori infection and NSAID or low-dose ASA use is different. A systematic review including 25 different studies ( 7 ) concluded that there was synergism for the development of peptic ulcer disease between H pylori infection and NSAID use. When they looked specifically at ulcer bleeding, the RR for the interaction between these two factors was marginally additive. This metaanalysis had several limitations. For instance, the prevalence of H pylori infection could not be adjusted by age because of the lack of individual patients data; NSAID takers had various underlying disorders, and different control populations were used. Furthermore, definitions of patients exposed to NSAIDs or ASA were also diverse. Different definitions of ulcer could also be a source of bias. Finally, the conclusions drawn from subgroup analyses (like PUB) were limited by small sample sizes. Our case control study tried to solve most of these limitations. The presence of H. pylori infection in NSAID users increased the RR of PUB similar to the addition of each individual factor alone, suggesting that these two factors act independently and in an additive manner. Therefore, patients having these two factors are at an increased risk of developing a bleeding peptic ulcer event compared with patients taking NSAIDs alone or infected only by H. pylori. These results may have clear implications for clinical practice, as elimination of both factors is essential to maximally reduce the risk, and eradication of H. pylori infection among NSAID users should have an impact on the resulting risk. However, a different association was observed with low-dose ASA and H. pylori infection. Both were independent risk factors for PUB, but there was no suggestion of a positive interaction between these two factors. This also may have important clinical implications, as, based on these data, H. pylori eradication in low-dose ASA users should not have a major impact on the risk of developing PUB, which differs from previously reported studies ( ). Reasons for the difference in our findings with previous reports may be partly due to study designs, heterogeneous patient populations, validity of exposure information, and different clinical outcomes evaluated. Actually, the vast majority of data concerning the interaction between H. pylori and low-dose ASA are for the most part limited to Asian population and to extrapolation of data from studies evaluating NSAIDs, despite major mechanistic differences between the two types of agents. Only two randomized controlled trials (RCTs) have been published on this issue with low-dose ASA ( 15 ), both of them in Asian population and for secondary prevention of UGIB: one from Chan and colleagues ( 14 ) and the other from Lai and colleagues ( 16 ). In addition, a recent systematic review by Fletcher et al. ( 17 ), including 13 studies, concluded that the current available evidence was insufficient to perform a meta-analysis and that no firm conclusion could be drawn regarding the impact of H. pylori on UGIB risk in low-dose ASA users. Our study provides additional evidence to evaluate this interaction. Compared with individuals free of H. pylori infection and no low-dose ASA use, the RR for PUB in low-dose ASA users and H. pylori -infected individuals was 2.2 and 2.8, respectively, with a similar increased risk when both factors are present (RR: 3.5), supporting no major interaction between low-dose ASA use and H. pylori infection for the development of UGIB. Another important finding concerning the interaction between these factors is ulcer location, as the pathogenesis of gastric and duodenal ulcers is somehow different ( 1 ). Most published studies did not separate patients by ulcer location and reported data for both ulcers together ( ). It is widely believed that NSAID intake increases the risk of gastric ulcer to a greater extent compared with duodenal ulcer, whereas the location of ulcers associated with H. pylori infection strongly depends on the distribution of gastritis, which in turn is related to the level of gastric acid output ( 2 ). Our analysis suggests that NSAID use alone has a greater effect in the development of gastric than duodenal ulcers (RR: 6.2 ( ) vs. 2.2 ( ), respectively), whereas the risk of duodenal ulcer related to H. pylori infection was greater compared 2015 by the American College of Gastroenterology The American Journal of GASTROENTEROLOGY

5 688 Sostres et al. with gastric ulcer (RR: 3.3 ( ) vs. 2.1 ( ), respectively): yet, it should be noted that all these difference were not statistically significant. The joint effect of NSAID use and H. pylori infection was additive for gastric ulcer bleeding and nearly synergistic for duodenal ulcer bleeding ( Table 3 ). However, the effect of low-dose ASA and H. pylori infection in gastric and duodenal ulcer seems, in some way, different. When examining the joint effect of lowdose ASA and H. pylori infection according to ulcer site, no interaction was observed with gastric ulcer bleeding and close to an additive effect with duodenal ulcer bleeding. Strengths of our study include the large sample size, the welldefined logistics of case ascertainment and control selection, the validation of the cause of the bleeding in all patients with the original clinical records, and the structured data collection methods of data on prescription and non-prescription drug consumption equally implemented among cases and controls. Limitations are H. pylori diagnosis based on serology, which may reflect not only present but also recent or past H. pylori infection. Yet, this minor misclassification will have equally applied to cases and controls and should not have an impact on the estimations of the RR. On the other hand, H. pylori status was determined among all cases and controls with the same method reducing internal variability, and, although the test showed good correlation with previous H. pylori tests used in former studies, no specific local validation was performed. Observational studies are always open to residual confounding that can not always be completely controlled. Here, we reported estimates of RR adjusted by most widely recognized independent risk factors. In addition, it is also important to mention that bleeding from the lower small intestine was not examined. In summary, our data provide additional evidence that NSAID use, low-dose ASA use, and H. pylori infection are all independent risk factors for the development of PUB due to either gastric or duodenal peptic ulcer. We have shown that there is at least an additive effect between H. pylori infection and NSAID use. More importantly, the data show no interaction between low-dose ASA and H. pylori infection for the development of bleeding peptic ulcer, especially gastric ulcer bleeding, which may have clear implications for clinical practice as low-dose ASA intake in patients infected by H. pylori will carry a similar risk of developing PUB to patients not infected by H. pylori, making unnecessary the eradication in this frequent clinical scenario. Therefore, prevention strategies in low-dose ASA users should be implemented based on the presence of other risk factors in this population. María Arruebo involved in patient collection, sample collection, and acquisition of data. Maria Teresa Arroyo involved in the study design, as well as the planning, conducting, interpretation of data, and in drafting/editing the manuscript. Luis Bujanda involved in patient collection, sample collection, and acquisition of data. Luis Alberto García-Rodriguez involved in the study design, as well as the planning, conducting, interpretation of data, and in drafting/ editing the manuscript. Angel Lanas involved in the study design, as well as the planning, conducting, interpretation of data, and in drafting/editing the manuscript. Financial support : The study was funded by the Official Spanish Agency, Instituto de Salud Carlos III, FIS grant PI08/1301, and the CIBERehd, which is supporting the salary of Patricia Carrera. Potential competing interests : L.A. García-Rodríguez has received research funding from AstraZeneca R&D and Bayer and has also received honoraria for serving on scientific advisory boards for Bayer. The institution of Angel Lanas has received funds from Bayer from investigator-initiated research, and Angel Lanas has been advisor to Pfizer and Bayer and received speaking fees from Bayer and AstraZeneca. The remaining authors declare no conflict of interest. Study Highlights WHAT IS CURRENT KNOWLEDGE NSAID/ASA use and Helicobacter pylori ( H. pylori ) infection are independent risk factors for the development of peptic ulcers. The true effect of the interaction between these factors and peptic ulcer bleeding (PUB) is still unclear. H. pylori eradication in naive nonsteroidal anti-inflammatory drug (NSAID) users is associated with a significant reduction in the incidence of endoscopic ulcers in patients starting NSAIDs. The effect of H. pylori eradication on the incidence of endoscopic ulcers in naive aspirin (ASA) users is unknown. Current European and US guidelines recommend test and treat H. pylori infection in NSAID or ASA users who are at risk of PUB. WHAT IS NEW HERE There is an additive interaction between H. pylori infection and NSAID use on the risk of PUB. There is no interaction between low-dose ASA use and H. pylori infection for the development of PUB. These data suggest that H. pylori eradication might not reduce the risk of low-dose ASA-related PUB. CONFLICT OF INTEREST Guarantor of the article : Carlos Sostres, MD. Specific author contributions : Carlos Sostres involved in the study design, as well as the planning, conducting, interpretation of data, and in drafting/editing the manuscript. Patricia Carrera involved in statistical analysis, interpretation of data, and drafting/ editing the manuscript. Rafael Benito involved in the performance of serological determination of Helicobacter pylori infection, analysis, and interpretation of data. Pilar Roncales involved in patient collection, sample collection, and acquisition of data. REFERENCES 1. Hunt R, Bazzoli F. Review article: should NSAID low-dose aspirin takers be tested routinely for H. pylori infection and treated if positive? Implications for primary risk of ulcer and ulcer relapse after initial healing. Aliment Pharmacol Ther 2004 ;19 : Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. The Lancet 2009 ;374 : Baigent C, Blackwell L, Collins R et al. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009 ; 373 : The American Journal of GASTROENTEROLOGY VOLUME 110 MAY

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